1. Field of the Invention
The present invention relates to a novel use of a compound, Anisomelic acid (AA) isolated from Anisomeles malabarica. In particular, the present invention concerns pharmaceutical compositions of Anisomelic acid. The present invention also discloses the use of Anisomelic and compositions thereof in anti-viral cancer therapy.
2. Description of Related Art
Cervical cancer is the second most frequent malignancy affecting women worldwide, with approximately 500,000 new cases diagnosed and 280,000 deaths each year. Although surgery and chemo-radiotherapy can cure 80-95% of women with early stage cancer and 60% of loco-regionally advanced cancer, the recurrent and metastatic disease remains the major cause of cancer death. The current cytotoxic treatment options for advanced and metastatic cancer demonstrate modest results, with response rates of maximum 30% and overall survival of less than 10 months. Given this limited degree of success with conventional therapies, interest has increased in other therapeutic alternatives for cervical cancers.
Most cervical cancers are caused by infection with a range of high-risk ‘oncogenic’ Human Papilloma Virus (HPV) types, and it is now accepted that more than 99% of cervical cancer is initiated by HPV infection. Persistent HPV infections lead to a sequel of various grades of cervical dysplasia and also cervical cancer. The major high risk genotypes associated with cervical cancer are HPV 16 and 18, and these two together are responsible for approximately 70% of cervical cancers.
Integration of the HPV viral genome and expression of E6 and E7 viral proteins are critical steps in the development of this cancer. Elimination of the trophic sentinel response by E6 protein occurs through several important mechanisms. The best characterized mechanism involves the inactivation and degradation of the tumor suppressor p53. E6 undermines the tumor suppressor function of p53 through formation of a complex with a cellular protein called E6-associated protein (E6-AP). As a result, the G1/S and G2/M cell cycle checkpoints are lost, and the cell is susceptible to genomic instability that may allow for development of neoplasia.
High-risk E6 also activates telomerase which prevents the erosion of telomeres and allows the host cell to continue through many rounds of division without damage to the DNA. E6 has also been reported to activate nuclear factor kappa B (NF-κB) leading to enhanced expression of Inhibitor of apoptosis protein 2 (IAP2) in HPV16 E6-immortalized human oral keratinocytes and primary human airway epithelial cells. It has also been observed that depletion of c-IAP2 leads to cell death, suggesting that HPV16-induced c-IAP2 expression is necessary for maintenance of the immortalized phenotype.
A second gene that is expressed very early in HPV infection is E7. E7 protein is pivotal to maintenance of the viral genome following entry into the host cell, and one of the most important functions is its ability to bind to the retinoblastoma tumor suppressor (Rb) family of cellular proteins. E7 simulates the phosphorylation and inactivation of pRb by binding to and targeting it to the proteosome for degradation. E2F transcription factors are then free to carry the tumor cell into S-phase. E7 interacts with p21Cip and p27Kip, and so interferes with their ability to inhibit cyclin-cdk activity and subsequently the cell cycle. Thus, E7 protein plays a large role in the maintenance of a cellular environment hospitable for viral replication.
In the continuing search for agents that may treat or ameliorate the affliction of cancer, natural products have provided an endless supply of active compounds that are increasingly being exploited. Several plant-derived compounds are currently successfully employed in cancer treatment.
Anisomelic acid is a diterpenoid isolated from Anisomeles malabarica (L.) R. Br., a herb belonging to the family Labiatae. This plant, commonly called Malabar catmint, is recommended in ancient medicines for use in catarrh, intermittent fever, bowel disorder and cancer. Aqueous ethanolic (50%) extracts of the plant have been shown to possess anticancer activity.
So far, Anisomelic acid as such has not been suggested or used for anti-viral cancer treatment.